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This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7–10% (53–86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was −9·6% (SE 0·4) with semaglutide 2·4 mg vs −3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was −6·2 percentage points (95% CI −7·3 to −5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. Novo Nordisk.

In patients with type 2 diabetes and chronic kidney disease, weekly semaglutide significantly reduced risks of major kidney events, cardiovascular events, and death from any cause while slowing loss of kidney function.

This open-label, 40-week, phase 3 trial assessed the efficacy and safety of tirzepatide, a weekly dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist under development for type 2 diabetes. Tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks.

GLP-1 receptor agonists and amylin receptor agonists have shown clinically relevant weight loss and glucose-lowering effects in people with overweight, obesity, and type 2 diabetes. Amycretin is a novel, single-molecule GLP-1 receptor and amylin receptor agonist. We aimed to investigate the safety, tolerability, pharmacokinetic properties, and pharmacodynamic effects of single ascending doses (part A) and multiple ascending doses (parts B and C/D) of amycretin in adult participants with overweight or obesity. In this phase 1, first-in-human, randomised, double-blind, placebo-controlled multipart study, participants were recruited at a single clinical research unit in San Antonio (TX, USA). Eligible individuals were men or women (including women of childbearing potential) aged 18–55 years at the time of signing informed consent with a BMI of 25·0–34·9 kg/m2 for parts A and B and a BMI of 27·0–39·9 kg/m2 for part C/D. For part A, participants were randomly assigned across six treatment groups (single ascending doses of oral amycretin [1 mg, 3 mg, 6 mg, 12 mg, 18 mg (12 + 6 mg per adaptive study design), or 25 mg]) or placebo (6:2 to amycretin groups vs placebo). Part A consisted of a 28-day screening period, a 1-day (single dose) intervention period, and a 21-day follow-up period. In part B, participants were randomly assigned across three treatment groups (multiple ascending doses of oral amycretin [3 mg, 6 mg, or 12 mg once daily]) or placebo (9:3 to amycretin groups vs placebo). Part B consisted of a 28-day screening period, a 10-day intervention period, and a 21-day follow-up period. In part C/D, 60 participants were randomly assigned to one of three dose-escalation treatment groups (multiple ascending doses of oral amycretin in a fixed titration regimen for all participants [part C1: from 3 mg to 50 mg once daily; part C2: from 6 mg to 2 × 50 mg (two tablets in a single daily dose); and part D: from 3 mg to 2 × 25 mg (two tablets in a single daily dose)]), or placebo (16:4 to amycretin groups vs placebo). Part C/D consisted of a 4-week screening period, a 12-week intervention period, and a 3-week follow-up period. The primary endpoint was the number of treatment-emergent adverse events reported from before dosing on day 1 (baseline) until the end-of-study visit on day 22 (part A), day 31 (part B), or day 105 (part C/D). Supportive secondary pharmacokinetic endpoints for parts A–D were area under the amycretin plasma concentration–time curve and maximum plasma concentration. Exploratory pharmacodynamic endpoints in part C/D were change in bodyweight (%) and fasting plasma glucose (mmol/L) from before dosing on day 1 until day 85. The safety analysis set, comprising all participants who were exposed to treatment, was used to analyse the endpoints and assessments related to safety. The full analysis set, comprising all randomly assigned participants, was used to analyse endpoints related to pharmacokinetic and exploratory pharmacodynamic endpoints. This study is registered with ClinicalTrials.gov, NCT05369390. Between May 11, 2022, and Jan 9, 2024, 144 participants were enrolled in the study (48 participants in part A, 36 participants in part B, and 60 participants in part C/D). Across parts A–D, there were 364 treatment-emergent adverse events in 89 (62%) of 144 participants, all of which were mild or moderate in severity and increased in frequency in a dose-dependent manner. The most common treatment-emergent adverse events were gastrointestinal in nature (180 [49%] of 364 events), observed in 72 (81%) of 89 participants who reported a treatment-emergent adverse event. No deaths were reported. Amycretin plasma concentrations were consistent with dose proportionality across all treatment groups. In people with overweight or obesity, amycretin appeared safe and tolerable. Results from this first-in-human, phase 1 study support further investigation of the weight loss properties of amycretin. Novo Nordisk A/S.

This trial randomly assigned pregnant women with type 1 diabetes to standard insulin therapy with continuous glucose monitoring or to hybrid closed-loop therapy. The latter significantly improved maternal glycemic control.

In a 13-week, randomized trial involving persons 6 to 79 years of age with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction in the glycated hemoglobin level than standard care.

Closed-loop control systems of insulin delivery may improve glycemic outcomes in young children with type 1 diabetes. The efficacy and safety of initiating a closed-loop system virtually are unclear. In this 13-week, multicenter trial, we randomly assigned, in a 2:1 ratio, children who were at least 2 years of age but younger than 6 years of age who had type 1 diabetes to receive treatment with a closed-loop system of insulin delivery or standard care that included either an insulin pump or multiple daily injections of insulin plus a continuous glucose monitor. The primary outcome was the percentage of time that the glucose level was in the target range of 70 to 180 mg per deciliter, as measured by continuous glucose monitoring. Secondary outcomes included the percentage of time that the glucose level was above 250 mg per deciliter or below 70 mg per deciliter, the mean glucose level, the glycated hemoglobin level, and safety outcomes. A total of 102 children underwent randomization (68 to the closed-loop group and 34 to the standard-care group); the glycated hemoglobin levels at baseline ranged from 5.2 to 11.5%. Initiation of the closed-loop system was virtual in 55 patients (81%). The mean (±SD) percentage of time that the glucose level was within the target range increased from 56.7±18.0% at baseline to 69.3±11.1% during the 13-week follow-up period in the closed-loop group and from 54.9±14.7% to 55.9±12.6% in the standard-care group (mean adjusted difference, 12.4 percentage points [equivalent to approximately 3 hours per day]; 95% confidence interval, 9.5 to 15.3; P<0.001). We observed similar treatment effects (favoring the closed-loop system) on the percentage of time that the glucose level was above 250 mg per deciliter, on the mean glucose level, and on the glycated hemoglobin level, with no significant between-group difference in the percentage of time that the glucose level was below 70 mg per deciliter. There were two cases of severe hypoglycemia in the closed-loop group and one case in the standard-care group. One case of diabetic ketoacidosis occurred in the closed-loop group. In this trial involving young children with type 1 diabetes, the glucose level was in the target range for a greater percentage of time with a closed-loop system than with standard care. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; PEDAP ClinicalTrials.gov number, NCT04796779.).

In a phase 3a trial involving adults with type 2 diabetes who had not previously received insulin, glycemic control was better with once-weekly insulin icodec than with once-daily insulin glargine U100.

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.